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Nature Genetics May 2015Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis...
Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.
Topics: Aged; Antineoplastic Agents; Benzoquinones; Carcinoma, Hepatocellular; Cell Line, Tumor; DNA Mutational Analysis; Exome; Female; Genetic Association Studies; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Liver Neoplasms; Male; Molecular Targeted Therapy; NAD(P)H Dehydrogenase (Quinone); Risk Factors; Sequence Deletion
PubMed: 25822088
DOI: 10.1038/ng.3252 -
International Journal of Biological... 2023Timosaponin AIII (Tim-AIII), a steroid saponin, exhibits strong anticancer activity in a variety of cancers, especially breast cancer and liver cancer. However, the...
Timosaponin AIII (Tim-AIII), a steroid saponin, exhibits strong anticancer activity in a variety of cancers, especially breast cancer and liver cancer. However, the underlying mechanism of the effects of Tim-AIII-mediated anti-lung cancer effects remain obscure. In this study, we showed that Tim-AIII suppressed cell proliferation and migration, induced G2/M phase arrest and ultimately triggered cell death of non-small cell lung cancer (NSCLC) cell lines accompanied by the release of reactive oxygen species (ROS) and iron accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion. Interestingly, we found that Tim-AIII-mediated cell death was reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Meanwhile, the heat shock protein 90 (HSP90) was predicted and verified as the direct binding target of Tim-AIII by SwissTargetPrediction (STP) and surface plasmon resonance (SPR) assay. Further study showed that Tim-AIII promoted HSP90 expression and Tim-AIII induced cell death was blocked by the HSP90 inhibitor tanespimycin, indicating that HSP90 was the main target of Tim-AIII to further trigger intracellular events. Mechanical analysis revealed that the Tim-AIII-HSP90 complex further targeted and degraded glutathione peroxidase 4 (GPX4), and promoted the ubiquitination of GPX4, as shown by an immunoprecipitation, degradation and ubiquitination assay. In addition, Tim-AIII inhibited cell proliferation, induced cell death, led to ROS and iron accumulation, MDA production, GSH depletion, as well as GPX4 ubiquitination and degradation, were markedly abrogated when HSP90 was knockdown by HSP90-shRNA transfection. Importantly, Tim-AIII also showed a strong capacity of preventing tumor growth by promoting ferroptosis in a subcutaneous xenograft tumor model, whether C57BL/6J or BALB/c-nu/nu nude mice. Together, HSP90 was identified as a new target of Tim-AIII. Tim-AIII, by binding and forming a complex with HSP90, further targeted and degraded GPX4, ultimately induced ferroptosis in NSCLC. These findings provided solid evidence that Tim-AIII can serve as a potential candidate for NSCLC treatment.
Topics: Animals; Humans; Mice; Carcinoma, Non-Small-Cell Lung; Ferroptosis; HSP90 Heat-Shock Proteins; Iron; Lung Neoplasms; Mice, Inbred C57BL; Mice, Nude; Reactive Oxygen Species; Saponins; Steroids; Ubiquitination
PubMed: 37056925
DOI: 10.7150/ijbs.77979 -
Haematologica Nov 2011In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well...
BACKGROUND
In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia.
DESIGN AND METHODS
Patients received cytarabine 400 mg/m(2)/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients.
RESULTS
Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m(2)/day for 5 days along with tanespimycin 300 mg/m(2) on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest.
CONCLUSIONS
Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).
Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzoquinones; Checkpoint Kinase 1; Cytarabine; Female; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Leukemia; Male; Middle Aged; Protein Kinases; Recurrence; Time Factors
PubMed: 21791475
DOI: 10.3324/haematol.2011.049551 -
Cell Reports May 2021Communication between biological components is critical for homeostasis maintenance among the convergence of complicated bio-signals. For therapeutic nanoparticles...
Communication between biological components is critical for homeostasis maintenance among the convergence of complicated bio-signals. For therapeutic nanoparticles (NPs), the general lack of effective communication mechanisms with the external cellular environment causes loss of homeostasis, resulting in deprived autonomy, severe macrophage-mediated clearance, and limited tumor accumulation. Here, we develop a multistage signal-interactive system on porous silicon particles through integrating the Self-peptide and Tyr-Ile-Gly-Ser-Arg (YIGSR) peptide into a hierarchical chimeric signaling interface with "don't eat me" and "eat me" signals. This biochemical transceiver can act as both the signal receiver for amantadine to achieve NP transformation and signal conversion as well as the signal source to present different signals sequentially by reversible self-mimicking. Compared with the non-interactive controls, these signal-interactive NPs loaded with AS1411 and tanespimycin (17-AAG) as anticancer drugs improve tumor targeting 2.8-fold and tumor suppression 6.5-fold and showed only 51% accumulation in the liver with restricted hepatic injury.
Topics: Cell Communication; Humans; Models, Molecular; Nanoparticles; Neoplasm Staging; Neoplasms; Signal Transduction
PubMed: 34038723
DOI: 10.1016/j.celrep.2021.109131 -
Clinical Cancer Research : An Official... Jul 2010Heat shock protein (Hsp) 90 inhibition affects the Raf kinase signaling pathway and could enhance antitumor effects of sorafenib, a Raf kinase inhibitor. The combination...
PURPOSE
Heat shock protein (Hsp) 90 inhibition affects the Raf kinase signaling pathway and could enhance antitumor effects of sorafenib, a Raf kinase inhibitor. The combination of sorafenib and tanespimycin [17-allyl-amino-geldanamycin (17-AAG); NSC 330507/KOS-953] was evaluated in a phase I trial with the primary objective of defining a phase II dose.
PATIENTS AND METHODS
The dose cohorts consisted of fixed continuous oral dosing of 400 mg sorafenib twice daily, starting at 14 days before tanespimycin, which was administered intravenously at escalating doses (starting at 300 mg/m,(2) with 50 mg/m(2) increments), on days 1, 8, and 15 in a 28-day cycle. Toxicity was assessed weekly, and response was evaluated every two cycles.
RESULTS
Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were renal cancer (12), melanoma (6), and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in one patient each were observed at 450 mg/m(2) of tanespimycin. One hundred fourteen cycles were administered with a median of four cycles (range 1-17 cycles). Plasma concentrations of sorafenib and metabolites reached steady state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients
CONCLUSIONS
Recommended phase II doses of this combination are 400 mg sorafenib twice daily and 400 mg/m(2) tanespimycin on days 1, 8, and 15, every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Benzoquinones; Clinical Trials, Phase II as Topic; Cohort Studies; Colorectal Neoplasms; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Lactams, Macrocyclic; Male; Melanoma; Middle Aged; Niacinamide; Phenylurea Compounds; Pyridines; Sorafenib; Survival Analysis
PubMed: 20525756
DOI: 10.1158/1078-0432.CCR-10-0503 -
PloS One 2013Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a...
BACKGROUND
Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo.
METHODOLOGY/PRINCIPAL FINDINGS
Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles.
CONCLUSIONS/SIGNIFICANCE
We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.
Topics: Animals; Benzoquinones; Cell Line, Tumor; Disease Models, Animal; Drug Carriers; Female; Humans; Lactams, Macrocyclic; Metabolome; Metabolomics; Mice; Micelles; Nanoparticles; Ovarian Neoplasms; Paclitaxel; Spectroscopy, Near-Infrared; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 23505544
DOI: 10.1371/journal.pone.0058619 -
Cancer Cell International 2020Reversible acetylation of α-tubulin has been implicated in modulating microtuble structures and functions, which may subsequently involve in cellular apoptosis and...
BACKGROUND
Reversible acetylation of α-tubulin has been implicated in modulating microtuble structures and functions, which may subsequently involve in cellular apoptosis and autophage. But how to trigger apoptosis or autophage at what level of acetylated α-tubulin (Ac-α-tubulin) are not known. This study aims to demonstrate the dual functions and molecular mechanisms of α-tubulin acetylation in cellular apoptosis and autophage induced by tanespimycin in Calu-1 cells simultaneously.
METHODS
Calu-1 cells were treated with tanespimycin alone or combined administrations of different agents (including TSA, Docetaxel, Rapamycin, 3-MA and Z-vad) respectively and cell lysates were prepared to detect the given proteins by Western Blot. The cell survival was observed by inverted phase contrast microscope and estimated by SRB assay. HDAC6, TAT1 and Hsp90α/β proteins were knocked down by siRNA technique.
RESULTS
By combination administration of tanespimycin with TSA or Docetaxel, the expression of Ac-α-tubulin and cellular apoptosis were enhanced markedly. While combination of tanespimycin and Rapamycin, α-tubulin acetylation and apoptosis were inhibited, but LC3B-II expression was facilitated substantially. When tanespimycin was combined with autophage inhibitor 3-MA, α-tubulin acetylation elevation was apparently, but LC3B-II was attenuated. Apoptosis inhibitor Z-vad blocked partially Caspases activation induced by tanespimycin, but failed to hinder α-tubulin acetylation elevation. According to results of RNA interference, acetyltransferase TAT1, deacetylase HDAC6 and Hsp90 modulated the expression level of α-tubulin acetylation.
CONCLUSION
We have elucidated that acetylation of α-tubulin induced by tanespimycin has dual functions in cellular apoptosis and autophage and the level of α-tubulin acetylation reaches a degree Calu-1 cells undergo cell apoptosis rather than autophage, implying that the level of acetylated α-tubulin may determine cell fate for survival or apoptosis.
PubMed: 32774163
DOI: 10.1186/s12935-020-01453-y -
British Journal of Haematology Jun 2011This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor...
This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m(2) )+ bortezomib (0·7-1·3 mg/m(2) ) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m(2) and bortezomib at 1·3 mg/m(2) . Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzoquinones; Boronic Acids; Bortezomib; Dose-Response Relationship, Drug; Female; Humans; Lactams, Macrocyclic; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Pyrazines; Recurrence; Treatment Outcome
PubMed: 21534941
DOI: 10.1111/j.1365-2141.2011.08664.x -
Cell Death & Disease Dec 2023HSP90 has emerged as an appealing anti-cancer target. However, HSP90 inhibitors (HSP90i) are characterized by limited clinical utility, primarily due to the resistance...
HSP90 has emerged as an appealing anti-cancer target. However, HSP90 inhibitors (HSP90i) are characterized by limited clinical utility, primarily due to the resistance acquisition via heat shock response (HSR) induction. Understanding the roles of abundantly expressed cytosolic HSP90 isoforms (α and β) in sustaining malignant cells' growth and the mechanisms of resistance to HSP90i is crucial for exploiting their clinical potential. Utilizing multi-omics approaches, we identified that ablation of the HSP90β isoform induces the overexpression of HSP90α and extracellular-secreted HSP90α (eHSP90α). Notably, we found that the absence of HSP90α causes downregulation of PTPRC (or CD45) expression and restricts in vivo growth of BCR-ABL1+ leukemia cells. Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.
Topics: Humans; Antineoplastic Agents; HSP90 Heat-Shock Proteins; Leukemia; Mutation; Neoplasms; Drug Resistance, Neoplasm
PubMed: 38057328
DOI: 10.1038/s41419-023-06337-3 -
The FEBS Journal Aug 2017The molecular chaperone heat shock protein 90 (Hsp90α) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the...
The molecular chaperone heat shock protein 90 (Hsp90α) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ataxia-telangiectasia-mutated kinase (ATM) and nibrin (NBN), but not 53BP1, RAD50, and MRE11, are Hsp90α clients as the Hsp90α inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cell lines. Hsp90α-ATM and Hsp90α-NBN complexes are present in unstressed and irradiated cells, allowing the maintenance of ATM and NBN stability that is required for the MRE11/RAD50/NBN complex-dependent ATM activation and the ATM-dependent phosphorylation of both NBN and Hsp90α in response to IR-induced DNA double-strand breaks (DSBs). Hsp90α forms a complex also with ph-Ser1981-ATM following IR. Upon phosphorylation, NBN dissociates from Hsp90α and translocates at the DSBs, while phThr5/7-Hsp90α is not recruited at the damaged sites. The inhibition of Hsp90α affects nuclear localization of MRE11 and RAD50, impairs DDR signaling (e.g., BRCA1 and CHK2 phosphorylation), and slows down DSBs repair. Hsp90α inhibition does not affect DNA-dependent protein kinase (DNA-PK) activity, which possibly phosphorylates Hsp90α and H2AX after IR. Notably, Hsp90α inhibition causes H2AX phosphorylation in proliferating cells, this possibly indicating replication stress events. Overall, present data shed light on the regulatory role of Hsp90α on the DDR, controlling ATM and NBN stability and influencing the DSBs signaling and repair.
Topics: Amino Acid Substitution; Ataxia Telangiectasia Mutated Proteins; Benzoquinones; Cell Cycle Proteins; Cell Line, Transformed; Cells, Cultured; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Breaks, Double-Stranded; DNA Repair; Gene Deletion; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Models, Biological; Nijmegen Breakage Syndrome; Nuclear Proteins; Phosphorylation; Point Mutation; Proteasome Endopeptidase Complex; Protein Multimerization; Protein Processing, Post-Translational; Protein Stability; RNA Interference; Ubiquitination
PubMed: 28631426
DOI: 10.1111/febs.14145